Cannabinoid receptor deficiencies drive immune response dynamics in infection.

This study investigated the roles of cannabinoid receptors 1 and 2 (CB1R and CB2R) in regulating host responses to in C57BL/6 mice. The absence of both receptors significantly impaired host resilience, as evidenced by increased weight loss, deteriorated body condition, and reduced survival following infection. Notably, CB1R deficiency resulted in more pronounced weight loss and heightened susceptibility to bacterial proliferation, as demonstrated by increased dissemination to organs. In addition, both CB1R and CB2R knockout mice exhibited alterations in immune cell recruitment and cytokine production. CB1R-KO mice displayed increased T cell and macrophage populations, whereas CB2R-KO mice showed a reduction in NK cells, indicating receptor-specific effects on immune cell mobilization. Cytokine profiling of macrophages post-infection revealed that CB1R-KO mice had reduced IL-10 levels, along with increased IL-6 and TGF-β, suggesting a dysregulated polarization state that combines pro-inflammatory and regulatory elements. In contrast, CB2R-KO mice exhibited a profile consistent with a more straightforward pro-inflammatory shift. Furthermore, microbiota analysis demonstrated that CB2R-KO mice experienced significant gut dysbiosis, including reduced levels of beneficial and species and an increase in pro-inflammatory species post-infection. Functional microbiome analysis further indicated declines in key metabolic pathways, such as the shunt, L-glutamine biosynthesis, and L-lysine biosynthesis, suggesting microbiota-driven immune dysregulation. Together, these findings highlight the distinct, non-redundant roles of CB1R and CB2R in modulating innate immunity, host defense, and microbiota composition during bacterial infections.